| CHARACTERIZATION
AND EVALUATION OF NOVEL CYP2A4 INHIBITORS AS ANTI-PROLIFERATIVE/PRO-DIFFERENTIATING
AGENTS TARGETED TOWARDS REFRACTORY PROSTATE CANCER.
Dr Paul Thompson University of Ulster, Department of Biomedical Sciences, Coleraine |
 |
Calcitriol, the physiologically active metabolite of vitamin D, in addition to its well characterized anti-rachitic properties, is also known to exert potent anti-cancer effects in tissues such as breast, colon and prostate. The application of calcitriol as a chemotherapeutic agent to the treatment of prostate cancer is limited by the development of drug resistance, particularly when the disease progresses to an aggressive form known as Hormone Refractory Prostate Cancer (HRPC).
Experimental evidence suggests that an underlying mechanism that contributes to calcitriol resistance in HRPC is increased levels of an enzyme known as CYP24A1. CYP24A1 is specifically concerned with the breakdown and inactivation of vitamin D-based molecules and an increased activity of this enzyme would lead to reduced levels of calcitriol available within the cell to exert anti-cancer effects.
This project intends to assess two classes of novel compounds that exhibit selective inhibition of CYP24A1 and to evaluate if they have the potential to restore growth regulatory responses upon treatment of HPRC cells with vitamin D. The project will be part of a collaborative programme between Dr Claire Simons of Cardiff University in whose lab the compounds have been synthesised, and Dr Paul Thompson at the University of Ulster. Dr Thompson will lead the assessment of how these compounds may restore the anti-cancer properties of calcitriol in a vitamin D resistant prostate cancer cell line, and decipher the molecular events that underlie this process.
As well as serving as a first step in the evaluation of the CYP24A1 inhbitors as potential new chemotherapeutic agents, the project will provide important insights into the molecular events that give rise to vitamin D resistance in HPRC, how it can be overcome, and identify which of the genetic components of this process may serve as potential future drug targets.
Research summary, 25 March 2008.
Project 2007/13